The invention pertains to heterocycle-substituted cyclohexylamine derivatives as N-Methyl-D-Aspartate Antagonists (NMDA).
Over excitation of NMDA receptor channel complexes on postsynaptic neurons following excessive release of glutamic acid from synaptosomes and glutamic acid from synaptosomes and glial cells result in a massive calcium ion influx into the neuronal cells, which leads to their death. This is believed to occur under ischemic or hypoxic conditions such as stroke, hypoglycemic, cardiac arrest and physical trauma An NMDA receptor antagonist might be therapeutically useful because it may minimize damage of the central nervous system induced by ischemic or hypoxic conditions. The NMDA receptor channel complex consists of at least three binding domains including glutamic acid (or NMDA) recognition site, channel blocking binding site, and strycinine-insensitive glycine binding type. Physiologically, a blockade of at least one of these sites terminates the channel opening of the NMDA receptor to prevent a calcium ion influx (Nagata tm et al., J. Med Chem., 1994;37:3956-3968).
Excessive excitation by neurotransmitters may be responsible for the loss of neurons in cerebral vascular disorders such as cerebral ischemia or cerebral infauxtion resulting in a range of conditions such as thromboembolic or hemorrhagic stroke, cerebral vasospasmn, hypoglycemia, cardiac arrest, status epilepticus, prenatal, asphyxia anoxia, such as from near drowning, pulmonary surgery, and cerebral trauma, as well as lathyrism, Alzeimer""s disease, and Huntington""s disease. Such conditions likewise suggest the use of agents that may act as antagonists in the receptors identified above may lead to treatment of amyotrophic lateral sclerosis (ALS), schizophrenia, parkinsonism, epilepsy, anxiety, pain, and drug addiction. PCT/EPO 94/01492 having publication number WO 94/26747 published Nov. 24, 1994, Watjen et al.
L-glutamic acid, L-aspartic acid and a number of other closely related amino acids have the ability to activate neurons in the nervous system and therefor the vast majority of excitatory neurons in the mammalian CNS. Interaction with glutamic acid mediated neurotransmission is considered a useful approach in the treatment of neurological and psychiatric diseases. WO 94/26746, published Nov. 24, 1994, Jacobsen, et al.
Excitatory amino acid receptor antagonists that block NMDA receptors are recognized for usefulness in the treatment of a variety of disorders. NMDA receptors are intimately involved in the phenomenon of excitotoxicity, which may be a critical determinant of outcome of several neurological disorders. Disorders known to be responsive to blockade of the NMDA receptor include acute cerebral ischemia (stroke or cerebral trauma, for example), muscular spasm, convulsive disorders, neuropathic pain and anxiety, and may be a significant causal factor in chronic neurodegenerative disorders such as Parkinson""s disease (Klockgether T., Turski L. Ann. Neurol., 1993;34:585-593), human immunodeficiency virus (HI) related neuronal injury, amyotrophic laterial sclerosis (ALS), Alzheimer""s disease (Francis P. T. Sims N. R, Procter A. W., Bowen D. M. J Neurochem., 1993;60(5):1589-1604), and Huntington""s disease (see Lipton S. TINS, 1993;16(12):527-532; Lipton S. A., Rosenberg P. A. New Eng. J. Med, 1994;330(9):613-622; and Bigge C. F. Biochem. Pharmacol., 1993;45:1547-1561 and references cited therein). NMDA receptor antagonists may also be used to prevent tolerance to opiate analgesia or to help control withdrawal symptoms from addictive drugs (European Patent Application 488,959A).
Many of the properties of native NMDA receptors are seen in recombinant homomeric NR1 receptors. These properties are altered by the NR2 subunits. Recombinant NMDA receptors expressed in Xenopus Oocytes have been studied by voltage-clamp recording, and has developmental and regional expression of the mRNAs encoding NMDA receptor subunits. Electrophysiological assays were utilized to characterize the actions of compounds at NMDA receptors expressed in Xenopus Oocytes. The compounds were assayed at four subunit combinations at cloned rat NMDA receptors, corresponding to three putative NMDA receptor subtypes (Moriyoshi et al. Nature, 1991; 354:31-37; Monyer et al. Science, 1992;256:1217-1221; Kutsuwada et al. Nature, 1992; 358:36-41; Sugihara et al. Biochem. Biophys Res. Comnmun., 1992;185:826-832).
Expression cloning of the first NMDA receptor subunit, NMDAR1 (NR1) in Nakanishi""s lab in 1991 provided an initial view of the molecular structure of the NMDA receptor (Moriyoshi, supra., 1991). There are several other structurally related subunits (NMDAR2A through NMDAR2D) that join NR1 in heteromeric assemblies to form the functional ion channel complex of the receptor (Annu. Rev. Neurosci., 1994:17;31-108). The molecular heterogeneity of NMDA receptors implies a future potential for agents with subtype selective pharmacology.
Described are heterocycle-substituted cyclohexylamines of Formula I and their pharmaceutically acceptable salts thereof 
wherein:
Ar is substituted 1 to 3 times or unsubstituted aryl or substituted 1 to 3 times or unsubstituted hereroaryl, which heteroaryl is from 5 to 14 atoms having from 1 to 2 heteroatoms selected from N, O, and S wherein the substituents are selected from the groups F, Cl, Br, I, OH, NH2, SH, CN, NO2, OCH3, OC(O)CH3, CF3, OCH2CH2OH, NHC(O)CH3, NHCH3, or N(CH3)2;
xe2x80x94Exe2x80x94Yxe2x80x94 is selected from the group consisting of
xe2x80x94CHxe2x95x90CHxe2x80x94N(H)xe2x80x94,
xe2x80x94(CH2)2xe2x80x94N(H)xe2x80x94,
xe2x80x94CHxe2x95x90Nxe2x80x94N(H)xe2x80x94,
xe2x80x94C(O)xe2x80x94CH2xe2x80x94N(H)xe2x80x94,
xe2x80x94CH2xe2x80x94C(O)xe2x80x94N(H)xe2x80x94,
xe2x80x94CH2xe2x80x94S(O)xe2x80x94N(H)xe2x80x94,
xe2x80x94CH2xe2x80x94S(O)2xe2x80x94N(H)xe2x80x94,
xe2x80x94CHxe2x95x90CHxe2x80x94CH(OH)xe2x80x94,
xe2x80x94(CH2)2xe2x80x94CH(OH)xe2x80x94,
xe2x80x94C(O)xe2x80x94CH2xe2x80x94C(O)xe2x80x94,
xe2x80x94C(O)xe2x80x94NHxe2x80x94C(O)xe2x80x94,
xe2x80x94Nxe2x95x90CHxe2x80x94N(H)xe2x80x94,
xe2x80x94N(H)xe2x80x94C(O)xe2x80x94N(H)xe2x80x94,
xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94,
xe2x80x94Sxe2x80x94C(O)xe2x80x94NHxe2x80x94,
xe2x80x94Oxe2x80x94Nxe2x95x90CH(OH)xe2x80x94,
xe2x80x94Sxe2x80x94Nxe2x95x90CH(OH)xe2x80x94,
xe2x80x94Nxe2x95x90Nxe2x80x94N(H)xe2x80x94,
xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90C(OH)xe2x80x94,
xe2x80x94(CH2)3xe2x80x94CH(OH)xe2x80x94,
xe2x80x94(CH2)2xe2x80x94S(O)xe2x80x94N(H)xe2x80x94,
xe2x80x94CH2)2xe2x80x94S(O)2xe2x80x94N(H)xe2x80x94,
xe2x80x94CHxe2x95x90CHxe2x80x94C(O)xe2x80x94N(H)xe2x80x94,
xe2x80x94C(O)xe2x80x94NHxe2x80x94Nxe2x95x90C(OH)xe2x80x94,
xe2x80x94CHxe2x95x90Nxe2x80x94NHxe2x80x94C(O),
xe2x80x94CHxe2x95x90N(O)xe2x80x94Nxe2x95x90C(OH)xe2x80x94,
xe2x80x94N(H)xe2x80x94C(O)xe2x80x94N(H)xe2x80x94C(O)xe2x80x94,
xe2x80x94Nxe2x95x90CHxe2x80x94C(O)xe2x80x94NHxe2x80x94,
xe2x80x94Oxe2x80x94CH2xe2x80x94C(O)xe2x80x94NHxe2x80x94,
xe2x80x94Sxe2x80x94CH2xe2x80x94C(O)xe2x80x94NHxe2x80x94, and
xe2x80x94N(H)xe2x80x94C(O)xe2x80x94C(O)xe2x80x94N(H)xe2x80x94; 
d is an integer from 0 to 2;
n is an integer from 1 to 6;
q is an integer from 0 to 6;
R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, OH, hydroxyalkyl, aminoalkyl, aralkyl, or N(R4)(R5) wherein R4 and R5 are independently selected from hydrogen, alkyl, aralkyl, heteroaryl, heteroaralkyl, aminoalkyl, hydroxyalkyl, and thioalkyl;
R is hydrogen, alkyl, C(O)R6, C(O)OR6, C(O)NHR6, -alkyl-C(O)NH2, aralkyl, (C3-C7 cyclo-alkyl)-alkyl, hydroxyalkyl, aminoalkyl, amino(hydroxy)alkyl, carboxyalkyl, heteroaralkyl, alkenylalkyl, or OH wherein R6 is alkyl or aralkyl;
X is independently selected from hydrogen or an electron withdrawing group; and * denotes cis or trans or a mixture thereof.
The invention also relates to compounds of Formula II 
or a pharmaceutically acceptable salt thereof
wherein:
Ar is substituted 1 to 3 times or unsubstituted aryl or substituted 1 to 3 times or unsubstituted heteroaryl, which heteroaryl is from 5 to 14 atoms having from 1 to 2 heteroatoms selected from N, O, and S wherein the substituents are selected from the groups F, Cl, Br, I, OH, NH2, SH, CN, NO2, OCH3, OC(O)CH3, CF3, OCH2CH2OH, NHC(O)CH3, NHCH3, or N(CH3)2;
xe2x80x94Exe2x80x94Yxe2x80x94 is selected from the group consisting of
xe2x80x94CHxe2x95x90CHxe2x80x94N(H)xe2x80x94,
xe2x80x94(CH2)2xe2x80x94N(H)xe2x80x94,
xe2x80x94CHxe2x95x90Nxe2x80x94N(H)xe2x80x94,
xe2x80x94C(O)xe2x80x94CH2xe2x80x94N(H)xe2x80x94,
xe2x80x94CH2xe2x80x94C(O)xe2x80x94N(H)xe2x80x94,
xe2x80x94CH2xe2x80x94S(O)xe2x80x94N(H)xe2x80x94,
xe2x80x94CH2xe2x80x94S(O)2xe2x80x94N(H)xe2x80x94,
xe2x80x94CHxe2x95x90CHxe2x80x94CH(OH)xe2x80x94,
xe2x80x94(CH2)2xe2x80x94CH(OH)xe2x80x94,
xe2x80x94C(O)xe2x80x94CH2xe2x80x94C(O)xe2x80x94,
xe2x80x94C(O)xe2x80x94NHxe2x80x94C(O)xe2x80x94,
xe2x80x94Nxe2x95x90CHxe2x80x94N(H)xe2x80x94,
xe2x80x94N(H)xe2x80x94C(O)xe2x80x94N(H)xe2x80x94,
xe2x80x94Oxe2x80x94C(O)xe2x80x94NHxe2x80x94,
xe2x80x94Sxe2x80x94C(O)xe2x80x94NHxe2x80x94,
xe2x80x94Oxe2x80x94Nxe2x95x90CH(OH)xe2x80x94,
xe2x80x94Sxe2x80x94Nxe2x95x90CH(OH)xe2x80x94,
xe2x80x94Nxe2x95x90Nxe2x80x94N(H)xe2x80x94,
xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90C(OH)xe2x80x94,
xe2x80x94(CH2)3xe2x80x94CH(OH)xe2x80x94,
xe2x80x94(CH2)2xe2x80x94S(O)xe2x80x94N(H)xe2x80x94,
xe2x80x94(CH2)2xe2x80x94S(O)2xe2x80x94N(H)xe2x80x94,
xe2x80x94CHxe2x95x90CHxe2x80x94C(O)xe2x80x94N(H)xe2x80x94,
xe2x80x94C(O)xe2x80x94NHxe2x80x94Nxe2x95x90C(OH)xe2x80x94,
xe2x80x94CHxe2x95x90Nxe2x80x94NHxe2x80x94C(O),
xe2x80x94CHxe2x95x90N(O)xe2x80x94Nxe2x95x90C(OH)xe2x80x94,
xe2x80x94N(H)xe2x80x94C(O)xe2x80x94N(H)xe2x80x94C(O)xe2x80x94,
xe2x80x94Nxe2x95x90CHxe2x80x94C(O)xe2x80x94NHxe2x80x94,
xe2x80x94Oxe2x80x94CH2xe2x80x94C(O)NHxe2x80x94,
xe2x80x94Sxe2x80x94CH2xe2x80x94C(O)xe2x80x94NHxe2x80x94, and
xe2x80x94N(H)xe2x80x94C(O)xe2x80x94C(O)xe2x80x94N(H)xe2x80x94; 
d is an integer from 0 to 2;
t is an integer from 1 to 3;
R1 and R2 are independently selected from hydrogen, alkyl, OH, hydroxyalkyl, aminoalkyl, thioalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, guanidinyl, (aminocarbonyl)alkyl-, carboxyalkyl-, (methylthio)alkyl-, or N(R4)(R5) wherein R4 and R5 are independently selected from hydrogen, alkyl, aralkyl, heteroaryl, heteroaralkyl, ureidoalkyl, aminoalkyl, hydroxyalkyl, or thioalkyl;
R3 is hydrogen, alkyl, OH, or aralkyl;
R is hydrogen, alkyl, C(O)R6, C(O)OR6, C(O)NHR6, -alkyl-C(O)NH2, aralkyl, (C3-C7 cyclo-alkyl)-alkyl, hydroxyalkyl, aminoalkyl, amino(hydroxy)alkyl, carboxyalkyl, heteroaralikyl, alkenylalkyl, or OH wherein R6 is alkyl or aralkyl;
X is independently selected from hydrogen or an electron withdrawing group; and * denotes cis or trams or a mixture thereof.
The invention also relates to compounds of Formula III where the substituents Exe2x80x94Y, X, d, R, R1, R2, W, V, and Ar are as defined for Formula I. 
The invention is also concerned with a pharmaceutical composition useful for treating disorders responsive to the selective blockade of N-methyl-D-aspartate receptor subtypes in a mammal, including a human, suffering therefrom which comprises a therapeutically effective amount of at least one compound of Formula I or Formula II or Formula III and the pharmaceutically acceptable salts thereof, optionally disorders as stroke, cerebral ischemia, trauma, hypoglycemia, neurodegenerative disorders, anxiety, depression, migraine headache, convulsions, aminoglycoside antibiotics-induced hearing loss, psychosis, glaucoma, CMV retinitis, opioid tolerance or withdrawal, chronic pain, or urinary incontinence.
The invention is also concerned with a method of treating disorders responsive to the selective blockade of the N-methyl-D-aspartate receptor subtypes in a mammal, including a human, suffering therefrom which comprises administering in unit dosage form, at least one compound represented by Formulas I-III or their pharmaceutically acceptable salts thereof.
In the compounds of the present invention preferred are compounds of Formula I or pharmaceutically acceptable salts thereof. More preferably are those compounds wherein:
X is independently selected from hydrogen or an electron withdrawing group selected from the group consisting of halogen, nitro, cyano, aminoalkyl, CF3, C(O)CH3, and haloalkyl.
More preferred are compounds of Formula I or pharmaceutically acceptable salts thereof wherein:
Ar is unsubstituted or substituted phenyl; 
X is independently selected from hydrogen or an electron withdrawing group selected from the group consisting of halogen, nitro, cyano, aminoalkyl, CF3, C(O)CH3, and haloalkyl; and
* denotes trans.
Still more preferred are compounds of Formula I or pharmaceutically acceptable salts thereof wherein: 
Ar is unsubstituted or substituted phenyl;
Z is as defined above and further a group whereby Ar and the nitrogen atom in Formula I are separated by from 2 to 4 atoms;
X is hydrogen or an electron withdrawing group selected from the group consisting of halogen, nitro, cyano, aminoalkyl, alkyl, CF3, C(O)CH3, and haloalkyl; and
* denotes trans.
Still more preferred are compounds of Formula I or pharmaceutically acceptable salts thereof wherein: 
wherein m is an integer from 1 to 3;
R is hydrogen, methyl, C(O)CH3, heteroaralkyl, (C3-C7 cycloalkyl) alkyl, H2NC(O) alkyl, or alkenylalkyl;
X is hydrogen; and
* denotes trans.
Also preferred is a compound of Formula I wherein * denotes cis.
Most preferred is a compound selected from those listed below:
6-[3-(trans-4-Phenylcyclohexylamino)propyl]-3H-benzoxazol-2-one;
6-{3-[trans-4-(4-Fluorophenyl)cyclohexylamino]propyl}-3H-benzoxazol-2-one;
6-[2-(trans-4-Phenylcyclohexylamino)ethylsulfanyl]-3H-benzoxazol-2-one;
5-{1-Hydroxy-2-[methyl(trans-4-phenylcyclohexyl)amino]ethyl}-1,3-dihydrobenzimidazol-2-one;
6-(3-{[trans-4-(4-Fluorophenyl)cyclohexyl]methylamino}propyl)-3H-benzoxazol-2-one;
6-(3-{[trans-4-(4-Fluorophenyl)cyclohexyl]ethylamino}propyl)-3H-benzoxazol-2-one;
5-[2-(cis-4-Phenylcyclohexylamino)ethoxy]-1,3-dihydrobenzimidazol-2-one;
5-[2-(trans-4-Phenylcyclohexylamino)ethoxy]-1,3-dihydrobenzimidazol-2-one; and
6-{Methyl[2-(trans-4-Phenylcyclohexylamino)ethyl]amino}-3H-benzoxazol-2-one.
Preferred are compounds of Formula II or pharmaceutically acceptable salts thereof wherein:
X is independently selected from hydrogen or an electron withdrawing group selected from the group consisting of halogen, nitro, cyano, aminoalkyl, CF3, C(O)CH3, and haloalkyl.
More preferred are compounds of Formula II or pharmaceutically acceptable salts thereof wherein:
Ar is unsubstituted or substituted phenyl; 
X is independently selected from hydrogen or an electron withdrawing group selected from the group consisting of halogen, nitro, cyano, aminoalkyl, CF3, C(O)CH3, and haloalkyl; and
* denotes trans.
Still more preferred are compounds of Formula II or phamaceutically acceptable salts thereof wherein: 
Ar is unsubstituted or substituted phenyl;
Ar and the nitrogen atom bearing R are separated by 3 or 4 atoms;
X is independently selected from hydrogen or an electron withdrawing group selected from the group consisting of halogen, nitro, cyano, CF3, C(O)CH3, and haloalkyl; and
* denotes trans.
Still more preferred are compounds of Formula II or pharmaceutically acceptable salts thereof wherein: 
R is hydrogen, C(O)CH3, H2NC(O) alkyl, alkenylalkyl, or methyl or heteroaralkyl or cycloalkyl (3-7 carbon atoms) alkyl;
X is hydrogen; and
* denotes trans.
Also preferred is a compound of Formula II wherein * denotes cis.
Another preferred compound is that of Formula II named 6-{methyl-[2-(4-phenyl-cyclohexylamino)-ethyl]-amino}-3H-benzoxazol-2-one.
Preferred are compounds of Formula III wherein:
X is independently selected from hydrogen or an electron withdrawing group selected from the group consisting of halogen, nitro, cyano, aminoalkyl, CF3, C(O)CH3, and haloalkyl.
Other preferred compounds of Formula III are wherein:
Ar is unsubstituted or substituted phenyl; 
X is independently selected from hydrogen or an electron withdrawing group selected from the group consisting of halogen, nitro, cyano, aminoalkyl, CF3, C(O)CH3, and haloalkyl; and
* denotes cis.
Other preferred compounds of Formula m are wherein:
Ar is unsubstituted or substituted phenyl; 
X is independently selected from hydrogen or an electron withdrawing group selected from the group consisting of halogen, nitro, cyano, aminoalkyl, CF3, C(O)CH3, and haloalkyl; and
* denotes trans.
Other preferred compounds of Formula I, II or III are wherein * denotes cis.
The diradical group Exe2x80x94Y must contain a hydrogen bond donor functionality.
The term xe2x80x9calkylxe2x80x9d means a straight or branched hydrocarbon radical having from 1 to 12 carbon atoms unless otherwise specified, also known as a C1-C12 alkyl, and includes, for example, methyl, ethyl, 1-propyl, and 2-propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl, 1,1-dimethylethyl, 1-pentyl, 2-pentyl, 3-pentyl, 2,2-dimethylpropyl, 1-hexyl, 2-hexyl, 3-hexyl, 4-methyl-1-pentyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 5-methyl-1-hexyl, 1-octyl, 2-octyl, 3-octyl, 4-octyl, 6-methyl-1-heptyl, 5,5-dimethylhexyl, 1-nonyl, 2-nonyl, 1-decyl, 2-decyl, 1-undecyl, 2-undecyl, 1-dodecyl, and 5-dodecyl. Alkyl groups may be unsubstituted or independently substituted by from 1 to 3 substituents selected from F, Cl, Br, I, OH, NH2, SH, CN, NO2, OCH3, OC(O)CH3, CF3, OCH2 CH2OH, NHC(O)CH3, NHCH3, or N(CH3)2.
Alkyl groups having two or more carbons may optionally contain 1 or 2 sites of unsaturation, the groups being known as alkenyl groups or radicals. Illustrative examples of an alkenyl group or radical having from 2 to 12 carbon atoms, also known as a C2 to C12 alkenyl, include ethenyl, 1-propenyl, 2-propenyl, 1-buten-1-yl, 2-buten-1-yl, 1-penten-1-yl, 2-penten-1-yl, 1-penten-3-yl, 1-penten-5-yl, 1-hexen-1-yl, 1-hexen4-yl, 2-hexen-1-yl, 3-hexen-1-yl, 2-octen-3-yl, 5-nonen-2-yl, 4undecen-4-yl, and 5-dodecen-2-yl.
The term xe2x80x9carylxe2x80x9d means an aromatic carbocyclic ring having from 6 to 10 carbon atoms. Illustrative examples of an aryl group or radical include phenyl, 1-naphthyl, and 2-naphthyl. Aryl groups may be unsubstituted or independently substituted by from 1 to 3 substituents selected from F, Cl, Br, I, OH, NH2, SH, CN, NO2, OCH3, OC(O)CH3, CF3, OCH2CH2OH, NHC(O)CH3, NHCH3, or N(CH3)2.
The term xe2x80x9caralkylxe2x80x9d means an aryl-alkyl-group or radical wherein aryl and alkyl have the meanings as defined above. Illustrative examples of an arylalkyl group or radical include benzyl, 4-fluorophenylmethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 3-methyl-3-phenylpropyl, 1-naphthylmethyl, 1-naphthylethyl, 3-(1-naphthyl)-propyl, 4-(1-naphthyl)-butyl, 4-(2-naphthyl)-butyl, 4-phenylheptyl, and 12-(2-hydroxyphenyl)-dodec-3-yl.
The term xe2x80x9c(C3-C7 cycloalkyl) alkylxe2x80x9d and xe2x80x9ccycloalkyl (3-7 carbon atoms) alkylxe2x80x9d means an xe2x80x9calkylxe2x80x9d group (as described above) substituted thereon by a cycloalkyl group of from 3 to 7 carbon atoms as cyclopentyl, cyclopropyl, cyclohexyl, or cycloheptyl.
The term xe2x80x9cheteroatomxe2x80x9d means nitrogen, oxygen, or sulfur.
The term xe2x80x9cheteroarylxe2x80x9d means an unsaturated monocyclic group or radical of 5 or 6 atoms, an unsaturated fused bicyclic group or radical of from 8 to 10 atoms, or an unsaturated fused tricyclic group or radical of from 11 to 14 atoms, the cyclic groups having 1 or 2 heteroatoms independently selected from O, N, or S. Heteroaryl does not contain a hydrogen bond donor group Exe2x80x94Y. Illustrative examples of monocyclicheteroaryl include 2- or 3-thienyl, 2- or 3-furanyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isoxazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 3-, or 4-pyrid 3- or 4-pyridazinyl, 2- or 3-pyrazinyl, and 2-, 4-, or 5-pyrimidinyl. Illustrative examples of bicyclicheteroaryl include 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 1-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]-thienyl, 2-, 4-, 5-, 6-, or 7-benzofuran, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzothiazolyl, and 1-benzimidazolyl. Illustrative examples of tricyclic heteroaryl include 1-, 2-, 3-, or 4-dibenzofuranyl, 1-, 2-, 3-, or 4-dibenzothienyl and 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-(1,2,3,4-tetrahydroacridinyl). All with the proviso that when Z in Formula I is attached via a heteroatom, Z is attached to a carbon atom of the heteroaryl group or radical. Heteroaryl groups may be unsubstituted or independently substituted by from 1 to 3 substituents selected from F, Cl, Br, I, OH, NH2, SH, CN, NO2, OCH3, OC(O)CH3, CF3, OCH2CH2OH, NHC(O)CH3, NHCH3, or N(CH3)2.
As used above, a fused bicyclic group or radical is a group wherein two ring systems share two and only two atoms.
As used above, a fused tricyclic group or radical is a group wherein three ring systems share four and only four atoms.
The term xe2x80x9cheteroarallylxe2x80x9d means a heteroaryl-alkyl-group or radical wherein heteroaryl and alkyl have the meanings as defined above. Illustrative examples of an heteroaralkyl group or radical include 4-pyridyl-methyl, (4-fluoroquinolin-2-yl)methyl, 2-(isoxazol-3-yl)ethyl, and 12-(5-chlorothiophen-2-yl)-dodec-3-yl.
The term xe2x80x9chalogenxe2x80x9d means bromine, chlorine, fluorine, or iodine.
The term xe2x80x9calkenylalkylxe2x80x9d means a (C2-C12 alkenyl)-(C1-C12 alkyl) group or radical wherein C1-C12 alkyl and C2-C12 alkenyl are as defined above.
The term xe2x80x9caminoalkylxe2x80x9d means an H2N-alkyl-group or radical wherein alkyl has the meaning as defined above, which is a substituted alkyl group or radical containing from 1 to 3 substituents wherein at least one substituent is xe2x80x94NH2.
The term xe2x80x9chydroxyalkylxe2x80x9d means an HO-alkyl-group or radical wherein alkyl has the meaning as defined above, which is a substituted alkyl group or radical containing from 1 to 3 substituents wherein at least one substituent is xe2x80x94OH.
The term xe2x80x9camino(hydroxy)alikylxe2x80x9d means an H2N(HO)-alkyl-group or radical wherein alkyl has the meaning as defined above, which is a substituted alkyl group or radical containing from 2 or 3 substituents wherein at least one substituent is OH and one substituent is xe2x80x94NH2.
The term xe2x80x9c(aminocarbonyl)alkylxe2x80x9d means an H2NC(O)-alkyl-group or radical wherein alkyl has the meaning as defined above, which is a substituted alkyl group or radical containing from 1 to 3 substituents wherein at least one substituent is xe2x80x94(O)Cxe2x80x94NH2.
The term xe2x80x9cthioalkylxe2x80x9d means an HS-alkyl-group or radical wherein alkyl has the meaning as defined above, which is a substituted alkyl group or radical containing from 1 to 3 substituents wherein at least one substituent is xe2x80x94SH.
The term xe2x80x9c(methylthio)-alkyl-xe2x80x9d means a CH3S-alkyl-group or radical wherein alkyl has the meaning as defined above, which is a substituted alkyl group or radical containing from 1 to 3 substituents wherein at least one substituent is xe2x80x94SCH3.
The term xe2x80x9ccarboxyalkylxe2x80x9d means an HO2C-alkyl-group or radical wherein alkyl has the meaning as defined above, which is a substituted alkyl group or radical containing from 1 to 3 substituents wherein at least one substituent is xe2x80x94CO2H.
The term xe2x80x9chaloalkylxe2x80x9d means a halogen-alkyl-group or radical wherein halogen and alkyl have the meanings as defined above, which is a substituted alkyl group or radical containing from 1 to 3 substituents wherein at least one substituent is selected from F, Cl, Br, or I.
The term xe2x80x9cureidoalkylxe2x80x9d means an H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94NH-alkyl-group or radical wherein alkyl has the meanings as defined above, which is a substituted alkyl group or radical containing from 1 to 3 substituents wherein at least one substituent is H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94.
The term xe2x80x9celectron withdrawing groupxe2x80x9d means a group or radical selected from halogen, nitro, cyano, alkyl, CF3, C(O)CH3, P(O)(Oxe2x80x94R9)2, SO2xe2x80x94R9, SO2NHR9, C(O)NR9R9xe2x80x2 wherein R9 is independently selected from C1-C6 alkyl or unsubstituted or substituted phenyl, xe2x80x94(Cxe2x95x90NH)xe2x80x94NH2, xe2x80x94(Cxe2x95x90NH)xe2x80x94O-alkyl, methoxymethyl, or haloalkyl, wherein the substituents may be F, Cl, Br, I, OH, NH2, SH, CN, NO2, OCH3, OC(O)CH3, CF3, OCH2CH2OH, NHC(O)CH3, NHCH3, or N(CH3)2.
The phrase xe2x80x9cheterocycle, which heterocycle is a carboxylic acid or an amide isosterexe2x80x9d means a 5- or 6-membered monocyclic ring containing from 1 to 4 heteroatoms selected from N, O, and S and providing a hydrogen bond donor moiety selected from NH, OH, and SH. Illustrative examples include the following structures: 
See also Greenwood J. R., Vaccarella G., Cooper H. R., Allan R. D., Johnston G. A. P. Internet Journal of Chemistry, 1998;1(38) (Chart 4). Additional examples are well-known to the skilled artisan. (See, for example, (i) Lipinski C. A. Annual Reports in Medicinal Chemistry, 1986;21 (Chapter 21, Chapter 27); (ii) Thomber C. W. Chen. Soc. Rev., 1979;8:563; (iii) Burger A. Progress in Drug Research., 1991;37:288-371.)
The term xe2x80x9centgegenxe2x80x9d means the stereoisomerism about a carbon-carbon double bond wherein the highest ranking substituent on each carbon are on opposite sides, which substituent ranking is based on the sequence rules of the Cahn-Ingold-Prelog system (March J., Advanced Organic Chemistry, 4th ed, John Wiley and Sons, New York, 1992:109, 127, and references cited therein).
The term xe2x80x9czusammenxe2x80x9d means the stereoisomerism about a carbon-carbon double bond wherein the highest ranking substituent on each carbon are on the same side, which substituent ranking is based on the sequence rules of the Cahn-Ingold-Prelog system (March J. Advanced Organic Chemistry, 4th ed., John Wiley and Sons, New York, 1992:109, 127, and references cited therein).
The term xe2x80x9ccisxe2x80x9d means the stereoisomerism about a carbon-carbon double bond, a monocyclic ring, a fused bicyclic ring, or a bridged bicyclic ring wherein the highest ranking substituent on each of the two carbons of relevance are on the same side, which substituent ranking is based on the sequence rules of the Cahn-Ingold-Prelog system (March J. Advanced Organic Chemistry, 4th ed., John Wiley and Sons, New York, 1992;109, 127-133, and references cited therein).
The term xe2x80x9ctransxe2x80x9d means the stereoisomerism about a carbon-carbon double bond, a monocyclic ring, a fused bicyclic ring, or a bridged bicyclic ring wherein the highest ranking substituent on each of the two carbons of relevance are on opposite sides, which substituent ranking is based on the sequence rules of the Cahn-Ingold-Prelog system (March J. Advanced Organic Chemistry, 4th ed., John Wiley and Sons, New York, 1992:109, 127-133, and references cited therein).
The terms xe2x80x9ccisxe2x80x9d or xe2x80x9ctransxe2x80x9d refers to the relative stereochemistry of the groups attached to the cyclohexyl rings of Formulas I or II at the carbon atoms denoted by xe2x80x9c*xe2x80x9d.
The term xe2x80x9c(X)dxe2x80x9d means the group X is present 1 or 2 times on the phenylene to which it is attached, which group is independently selected from hydrogen or an electron withdrawing group wherein the electron withdrawing group is as defined above unless otherwise stated. The groups X can be the same or different. 
wherein n is an integer of from 1 to 6 and q is an integer of from 0 to 6 mean a chain of from 1 to 6 carbons or from 0 to 6 carbons, respectively, wherein each carbon is independently substituted, which substituents are the groups R1 and R2, wherein R1 and R2 are independently (R1 and R2 in each occurrence can be the same or different) selected from the groups consisting of hydrogen, alkyl, OH, hydroxyalkyl, aminolkyl, aralkyl, or N(R4)(R5) wherein R4 and R5 are independently selected from hydrogen, alkyl, aralkyl, heteroaryl, heteroaralkyl, aminoalkyl, hydroxyalkyl and thioalkyl, unless otherwise stated. The groups R1 can be the same or different and the groups R2 can be the same or different.
For purposes of the syntheses of the compounds of the present invention, reactive functional groups present in starting materials, reaction intermediates, or reaction products may be protected during chemical reactions using protecting groups which render the reactive functional groups substantially inert to the reaction conditions (see for example, Green T. W., Wuts P. G. Protective Groups in Organic Synthesis, 2nd ed., John Wiley and Sons, New York, 1991). Thus, for example, protecting groups such as the following may be utilized to protect suitable amino, hydroxyl, and other groups of related reactivity: carboxylic acyl groups, such as formyl, acetyl, trifluoroacetyl; alkoxycarbonyl groups, such as ethoxycarbonyl, t-butoxycarbonyl (BOC), xcex2,xcex2,xcex2-trichloroethoxycarbonyl (TCEC), xcex2-iodoethoxycarbonyl; aryloxycarbonyl groups, such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, phenoxycarbonyl; trialkyl silyl groups, such as trimethylsilyl and t-butyldimethylsilyl (TBDMS); and groups such as trityl, tetrahydropyranyl, vinyloxycarbonyl, o-nitrophenylsulfenyl, diphenylphosphinyl, p-toluenesulfonyl, and benzyl may all be utilized. The protecting group may be removed, after completion of the synthetic reaction of interest, by procedures known to those skilled in the art. For example, a BOC group may be removed by acidolysis, a trityl group by hydrogenolysis, TBDMS by treatment with fluoride ions, and TCEC by treatment with zinc.
It is to be appreciated that the compounds of Formulas I-III may have chiral centers in which case, all stereoisomers thereof both separately and as racemic and/or diastereoisomeric mixtures are included.
Some of the compounds of Formulas I-III are capable of further forming pharmaceutically acceptable acid-addition and/or base salts. All of these forms are within the scope of the present invention.
Pharmaceutically acceptable acid addition salts of the compounds of Formula I include salts derived from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihyrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinates suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge S. M. et al. xe2x80x9cPharmaceutical Salts,xe2x80x9d Journal of Pharmaceutical Science, 1977;66:1-19).
The acid addition salt of said basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner.
Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N-dibenzylethylenediainine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge, supra., 1977).
The base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner.
Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
The compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compounds of the present invention can be administered by inhalation, for example, intranasally. Additionally, the compounds of the present invention can be administered transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of Formulas I-III or a corresponding pharmaceutically acceptable salt of a compound of Formulas I-III.
For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component.
In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
The powders and tablets preferably contain from 5 or 10 to about 70 percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term xe2x80x9cpreparationxe2x80x9d is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted, and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, and stabilizing and thickening agents as desired.
Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is divided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 100 mg preferably 0.5 mg to 100 mg according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.
In therapeutic use as antagonists or as agents for the treatment of diseases, the compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 0.01 mg to about 100 mg/kg daily. A daily dose range of about 0.01 mg to about 10 mg/kg is preferred. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.
Example 1, lactose and cornstarch (for mix) are blended to uniformity. The cornstarch (for paste) is suspended in 200 mL of water and heated with stirring to form a paste. The paste is used to granulate the mixed powders. The wet granules are passed through a No. 8 hand screen and dried at 80xc2x0 C. The dry granules are lubricated with the 1% magnesium stearate and pressed into a tablet. Such tablets can be administered to a human from one to four times a day for treatment of disease caused by over excitation of NMDA receptor channel complexes.
The compounds of the present invention can be prepared according to the various synthetic schemes that follow. Protecting groups may be used when appropriate throughout many of the schemes. Although specifically noted in certain schemes, the appropriate use and choice of protecting groups is well-known by one skilled in the art, and is not limited to the specific examples below. It is also understood that such groups not only serve to protect chemically reactive sites, but also to enhance solubility or otherwise change physical properties. A good general reference for protecting group preparation and deprotection is xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d by Theodora Green, supra, 1991. A number of general reactions such as oxidations and reductions are not shown in detail but can be done by methods understood by one skilled in the art. General transformations are well reviewed in xe2x80x9cComprehensive Organic Transformationxe2x80x9d by Richard Larock, and the series xe2x80x9cCompendium of Organic Synthetic Methodsxe2x80x9d (1989) published by Wiley-Interscience. In general, the starting materials were obtained from commercial sources unless otherwise indicated.
These compounds can be prepared following the procedures described in the examples below.
General Methods
HCl salts were prepared by treatment of a MeOH solution of the amine with excess HCl in Et2O. The salts were isolated either by filtration if they precipitated directly from the etherial solution, or by first removal of the solvent under reduced pressure, and then crystallization (Et2O/MeOH).
Purity was determined by reversed phase HPLC by the following methods:
Method A: column: YMC J""Sphere C18, ODS-M80, 150xc3x974.6 mm, 4xcexc; solvent A: 0.1% H3PO4 in H2O; solvent B: 0.1% H3PO4 in CH3CN; gradient: 10-100% B over 15 minutes; flow: 1 mL minxe2x88x921; detection: 210 nm.
Method B: column: YMC J""Sphere C18, ODS-M80, 150xc3x974.6 mm, 4xcexc; solvent A: 0.1% H3PO4 in H2O; solvent B: 0.1% H3PO4 in MeOH; gradient: 10-100% B over 15 minutes; flow: 1 mL minxe2x88x921; detection: 210 nm.